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CLINICAL STUDY PROTOCOL
Protocol Title: A Phase 3, Randomized, Stratified,
Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy,
Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in
Adults Aged 18 Years and Older
Protocol Number: mRNA-1273-P301
Sponsor Name:
Legal Registered Address:
ModernaTX, Inc. 200 Technology Square Cambridge, MA 02139
Sponsor Contact and
Medical Monitor:
Tal Zaks, MD, PhD, Chief Medical Officer ModernaTX, Inc. 200
Technology Square, Cambridge, MA 02139 Telephone: 1-617-209-5906
e-mail: [email protected]
Regulatory Agency
Identifier Number(s):
IND: 19745
Amendment Number: 3
Date of Amendment 3: 20 Aug 2020
Date of Amendment 2: 31 Jul 2020
Date of Amendment 1: 26 Jun 2020
Date of Original Protocol: 15 Jun 2020
CONFIDENTIAL
All financial and nonfinancial support for this study will be
provided by ModernaTX, Inc. The concepts and information contained
in this document or generated during the study are
considered proprietary and may not be disclosed in whole or in
part without the expressed written consent of ModernaTX, Inc. The
study will be conducted according to the
International Council for Harmonisation (ICH) Technical
Requirements for Registration of Pharmaceuticals for Human Use,
E6(R2) Good Clinical Practice (GCP) Guidance.
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PROTOCOL APPROVAL – SPONSOR SIGNATORY
Study Title: A Phase 3, Randomized, Stratified, Observer-Blind,
Placebo-Controlled Study to Evaluate the Efficacy, Safety, and
Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18
Years and Older
Protocol Number: mRNA-1273-P301
Protocol Version Date: 20 Aug 2020 Protocol accepted and
approved by: See esignature and date signed on
last page of document.
Tal Zaks, MD, PhD Chief Medical Officer ModernaTX, Inc. 200
Technology Square Cambridge, MA 02139 Telephone: 1-617-209-5906
Date
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DECLARATION OF INVESTIGATOR
I have read and understood all sections of the protocol entitled
“A Phase 3, Randomized, Stratified, Observer-Blind,
Placebo-Controlled Study to Evaluate the Efficacy, Safety, and
Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18
Years and Older” and the most recent version of the Investigator’s
Brochure.
I agree to supervise all aspects of the protocol and to conduct
the clinical investigation in accordance with the current Protocol,
the International Council for Harmonisation (ICH) Technical
Requirements for Registration of Pharmaceuticals for Human Use,
E6(R2) Good Clinical Practice (GCP) Guidance, and all applicable
government regulations. I will not make changes to the protocol
before consulting with ModernaTX, Inc. or implement protocol
changes without IRB/IEC approval except to eliminate an immediate
risk to participants.
I agree to administer study treatment only to participants under
my personal supervision or the supervision of a sub-investigator. I
will not supply study treatment to any person not authorized to
receive it. I also agree that persons debarred from conducting or
working on clinical studies by any court or regulatory agency will
not be allowed to conduct or work on studies for the Sponsor or a
partnership in which the Sponsor is involved. I will immediately
disclose it in writing to the Sponsor if any person who is involved
in the study is debarred, or if any proceeding for debarment is
pending, or, to the best of my knowledge, threatened.
I will not disclose confidential information contained in this
document including participant information, to anyone other than
the recipient study staffs and members of the IRB/IEC. I agree to
ensure that this information will not be used for any purpose other
than the evaluation or conduct of the clinical investigation
without the prior written consent from ModernaTX, Inc. I will not
disclose information regarding this clinical investigation or
publish results of the investigation without authorization from
ModernaTX, Inc.
The signature below provides the necessary assurance that this
study will be conducted according to all stipulations of the
protocol, including statements regarding confidentiality, and
according to local legal and regulatory requirements, US federal
regulations, and ICH E6(R2) GCP guidelines.
Signature of Principal Investigator Date
Printed Name of Principal Investigator
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Protocol Amendment Summary of Changes DOCUMENT HISTORY
Document Date
Amendment 3 20 Aug 2020 Amendment 2 31 Jul 2020 Amendment 1 26
Jun 2020 Original Protocol 15 Jun 2020
Amendment 3, 20 Aug 2020: Current Amendment
Main Rationale for the Amendment:
The main purpose of this amendment is to make changes to the
protocol in response to feedback from CBER.
The summary of changes table provided here describes the major
changes made in Amendment 3 relative to Amendment 2, including the
sections modified and the corresponding rationales. Minor editorial
or formatting changes are not included in this summary table. The
synopsis of Amendment 3 has been modified to correspond to changes
in the body of the protocol.
Summary of Major Changes from Protocol Amendment 2 to Protocol
Amendment 3:
Section # and Name Description of Change Brief Rationale
Title Page, Protocol Approval Page, Headers, Protocol Amendment
Summary of Changes
Updated the protocol version and date
To reflect the new version and date of the protocol
Section 5 (Study Population) Added a sentence to describe the
intent to enroll a representative sample of racial and ethnic
minority participants in the study
To enhance the diversity of the study population
Section 5.2 (Exclusion Criteria) Added clarification to
exclusion criterion #11 to define the parameters based on screening
CD4 count and viral load for exclusion of study participants
To clarify the definition of controlled HIV disease in the
exclusion criterion such that only participants with
well-controlled HIV disease are enrolled in the study
Section 5.2 (Exclusion Criteria) Removed “topical tacrolimus”
from exclusion criterion #12
No evidence to support any systemic effect of topical tacrolimus
to warrant excluding them
Section 6.2.1.1 (Stratification) Added HIV infection to the risk
factors at Screening
To stratify participants based on certain risk factors
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Section # and Name Description of Change Brief Rationale
Section 8.2.3 (Demographics/Medical History)
Added collection of risk factors for complications of
COVID-19
To document the diagnosis of any risk factor for complications
of COVID-19 used for stratification
Section 9.3 (Sample Size Determination)
Removed redundant bullet To remove redundancy in the assumptions
listed
Section 9.5.2 (Safety Analyses) Removed safety analysis by
serostatus
No added value for this analysis. Other subgroup analyses may be
specified in the SAP, as needed.
Section 9.5.5 (Subgroup Analyses) Removed the categories (white,
non-white) from the Race Variable
To allow for more refined Race categorization being collected in
the eCRF
Appendix 11.3 Removed “cessation of exogenous hormonal
therapy”
To allow post-menopausal women to take these medications if
needed for the treatment of the symptoms of menopause
Appendix 11.3 Removed “using hormonal contraception” from
postmenopausal female with high FSH levels
Not a standard of care for women for treatment of menopausal
symptoms
IRB and Regulatory Authority Approval A copy of this amended
protocol will be sent to the institutional review board (IRB) and
regulatory authority.
The changes described in this amended protocol require IRB
approval prior to implementation. In addition, if the changes
herein affect the informed consent, sites are required to update
and submit a revised informed consent for approval that
incorporates the changes described in this amended protocol.
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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Number: mRNA-1273-P301
Title: A Phase 3, Randomized, Stratified, Observer-Blind,
Placebo-Controlled Study to Evaluate the Efficacy, Safety, and
Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18
Years and Older.
Study Phase: 3 Objectives: Primary:
• To demonstrate the efficacy of mRNA-1273 to prevent
COVID-19.
• To evaluate the safety and reactogenicity of 2 injections of
mRNA-1273 given 28 days apart.
Secondary:
• To evaluate the efficacy of mRNA-1273 to prevent severe
COVID-19.
• To evaluate the efficacy of mRNA-1273 to prevent serologically
confirmed SARS-CoV-2 infection or COVID-19 regardless of
symptomatology or severity.
• To evaluate vaccine efficacy (VE) against a secondary
definition of COVID-19.
• To evaluate VE to prevent death caused by COVID-19. • To
evaluate the efficacy of mRNA-1273 to prevent COVID-19
after the first dose of investigational product (IP).
• To evaluate the efficacy of mRNA-1273 to prevent COVID-19 in
all study participants, regardless of evidence of prior SARS-CoV-2
infection.
• To evaluate the efficacy of mRNA-1273 to prevent asymptomatic
SARS-CoV-2 infection.
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Exploratory:
• To evaluate the effect of mRNA-1273 on the viral infection
kinetics as measured by viral load at SARS-CoV-2 infection
diagnosis by RT-PCR and number of days from the estimated date of
SARS-CoV-2 infection until undetectable SARS-CoV-2 infection by
RT-PCR.
• To assess VE to reduce the duration of symptoms of
COVID-19.
• To evaluate VE against all-cause mortality.
• To assess VE against burden of disease (BOD) due to
COVID-19.
• To evaluate the genetic and/or phenotypic relationships of
isolated SARS-CoV-2 strains to the vaccine sequence.
• To evaluate immune response markers after dosing with IP as
correlates of risk of COVID-19 and as correlates of risk of
SARS-CoV-2 infection.
• To conduct additional analyses related to furthering the
understanding of SARS-CoV-2 infection and COVID-19, including
analyses related to the immunology of this or other vaccines,
detection of viral infection, and clinical conduct.
Study Design and
Methodology: This is a Phase 3, randomized, stratified,
observer-blind, placebo-controlled study to evaluate the efficacy,
safety, and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine compared
to placebo in adults 18 years of age and older who have no known
history of SARS-CoV-2 infection but whose locations or
circumstances put them at appreciable risk of acquiring COVID-19
and/or SARS-CoV-2 infection. Figure 1 shows the study flow.
Participants will be randomly assigned to receive injections of
either 100 µg of mRNA-1273 vaccine or a placebo control in a 1:1
randomization ratio. Assignment will be stratified by age and
health risk. This is a case-driven study and thus final sample size
of the study will depend on the actual attack rate of COVID-19. All
participants will be assessed for efficacy and safety endpoints and
provide a nasopharyngeal (NP) swab sample and blood sample before
the first and second dose of IP in addition to a series of
post-dose blood samples for immunogenicity through 24 months after
the second dose of IP. Efficacy assessments will include
surveillance for COVID-19 with RT-PCR confirmation of SARS-CoV-2
infection after the first and second dose of IP. As noted above,
this is a case-driven study: if the prespecified criteria for early
efficacy are met at the time of either interim analysis or overall
efficacy at the primary
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analysis, a final study report describing the efficacy and
safety of mRNA-1273 will be prepared based on the data available at
that time. In the event that success criteria are met either at the
time of the interim analyses or when the total number of cases
toward the primary endpoint have accrued, participants will
continue to be followed in a blinded fashion until Month 25, to
enable assessment of long-term safety and durability of VE . If the
study concludes early, all participants will be requested to
provide a final blood sample at the time of study conclusion. All
participants may have up to 7 scheduled clinic visits, including
Screening, Day 1, Day 29, Day 57, Day 209, Day 394, and Day 759.
Each participant will receive 2 doses of IP by 0.5 mL intramuscular
(IM) injection, the first on Day 1 and the second on Day 29. An NP
swab sample will be collected prior to the first and second dose of
IP, for evaluation by RT-PCR. Participants will be given an
electronic diary (eDiary) to report solicited adverse reactions
(ARs) for 7 days after each dose of IP and to prompt an unscheduled
clinic visit for clinical evaluation and NP swab sample if a
participant experiences any symptoms of COVID-19. All participants
will receive safety calls on Day 8, Day 15, Day 22, Day 36, and Day
43 that will serve both to monitor for unsolicited AEs and to
monitor for symptoms of COVID-19. Surveillance for COVID-19 will be
performed through weekly contacts with the participant via a
combination of telephone calls and completion of an eDiary starting
at Day 1 through the end of the study. Participants with symptoms
of COVID-19 lasting at least 48 hours (except for fever and/or
respiratory symptoms) will return to the clinic or will be visited
at home by medically qualified site staff within 72 hours (an
“Illness Visit”) to collect an NP swab sample for RT-PCR testing
for SARS-CoV-2 and other respiratory pathogens, or alternatively,
if a clinic or home visit is not possible, will submit a saliva (or
nasal swab) sample for SARS-CoV-2 RT-PCR testing. Any confirmed
COVID-19 occurring in a participant will be captured as an MAAE
along with relevant concomitant medications and details about
severity, seriousness, and outcome. All confirmed COVID-19 cases
will be reported to the Sponsor or designee within 24 hours.
Starting with the Illness Visit, study participants will be
monitored by the study investigator (or appropriately delegated
study staff) for a 14-day period after diagnosis or until symptoms
resolve, whichever is later. Each participant diagnosed with
COVID-19 will monitor their body temperature, oxygen saturation,
and symptoms following the diagnosis of COVID-19. In addition to
daily follow-up of symptoms, assessments will include the
collection of saliva samples during the 28-day period following the
diagnosis of SARS-CoV-2 infection. The
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investigator will determine if medical attention is required due
to worsening of COVID-19. Finally, a convalescent visit will be
scheduled approximately 28 days after the initial Illness Visit. At
this visit, a saliva (or nasal swab) sample will be collected and a
blood sample will be drawn for immunologic assessment of SARS-CoV-2
infection. The 28-day period following the Illness Visit is
referred to as the Convalescent Period. If during the Convalescent
Period the participant has a positive result for SARS-CoV-2 from
the Illness Visit, the participant will continue the Convalescent
Period. If the participant has a negative result for SARS-CoV-2
from the Illness Visit, the participant will exit the Convalescent
Period, including discontinuation of daily telemedicine visits and
collection of saliva (or nasal swab) samples, and will return to
their respective study schedule. At each dosing visit, participants
will be instructed (Day 1) or reminded (Day 29) on how to document
and report solicited ARs in the eDiary provided. Solicited ARs will
be assessed for 7 days after each IP dose and unsolicited AEs will
be assessed for 28 days after each IP dose; SAEs, MAAEs, AEs
leading to withdrawal, will be assessed throughout the study.
Participants will have scheduled blood sampling (for immunogenicity
assessment) at Screening, Day 1, Day 29, Day 57, Day 209, Day 394,
and Day 759. This study will be conducted in compliance with the
protocol, Good Clinical Practice (GCP), and all applicable
regulatory requirements.
Randomization: Approximately 30,000 participants will be
randomly assigned in 1:1 ratio to receive either mRNA-1273 100 µg
or placebo. The randomization will be in a blinded manner using a
centralized Interactive Response Technology (IRT), in accordance
with pre-generated randomization schedules.
:
Randomization will be stratified based on age and, if they are
< 65 years of age, based on the presence or absence of risk
factors for severe illness from COVID-19 based on CDC
recommendation as of Mar 2020. There will be 3 strata for
randomization: ≥ 65 years, < 65 years and categorized to be at
increased risk (“at risk”) for the complications of COVID-19, and
< 65 years “not at risk”. Risk will be defined based on the
study participants’ relevant past and current medical history. At
least 25% of enrolled participants, but not more than 40%, will be
either ≥ 65 years of age or < 65 years of age and “at risk” at
Screening.
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Participants who are < 65 years old will be categorized as at
risk for severe COVID-19 illness if they have at least 1 of the
following risk factors at Screening:
• Chronic lung disease (eg, emphysema and chronic bronchitis,
idiopathic pulmonary fibrosis, and cystic fibrosis) or moderate to
severe asthma
• Significant cardiac disease (eg, heart failure, coronary
artery disease, congenital heart disease, cardiomyopathies, and
pulmonary hypertension)
• Severe obesity (body mass index ≥ 40 kg/m2)
• Diabetes (Type 1, Type 2 or gestational)
• Liver disease
• Human Immunodeficiency Virus (HIV) infection
Study
Population:
Participants (males and females 18 years of age or older at time
of consent), who are at risk of SARS-CoV-2 infection with no known
history of SARS-CoV-2 infection, are a subset of the planned target
population. Additionally, potential study participants at increased
risk of complications from COVID-19 will be included, since it is
hypothesized that these participants might derive the greatest
benefit from a vaccine. Participants ≥ 65 years of age will be
eligible for enrollment with or without underlying medical
conditions further increasing their risk of severe COVID-19. Study
sites may be selected based on SARS-COV-2 infection risk of the
local population. Approximately 30,000 participants will be
enrolled. The full lists of inclusion and exclusion criteria are
provided in the body of the protocol.
Efficacy
Assessments: Primary Efficacy Assessment:
To be considered as a case of COVID-19 for the evaluation of the
Primary Efficacy Endpoint, the following criteria must be met:
• The participant must have experienced at least TWO of the
following systemic symptoms: Fever (≥ 38ºC), chills, myalgia,
headache, sore throat, new olfactory and taste disorder(s), OR
• The participant must have experienced at least ONE of the
following respiratory signs/symptoms: cough, shortness of
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breath or difficulty breathing, OR clinical or radiographical
evidence of pneumonia; AND
• The participant must have at least one NP swab, nasal swab, or
saliva sample (or respiratory sample, if hospitalized) positive for
SARS-CoV-2 by RT-PCR.
Secondary Efficacy Assessments:
To be considered a severe COVID-19, the following criteria must
be met: a confirmed COVID-19 as per the Primary Efficacy Endpoint
case definition, plus any of the following:
• Clinical signs indicative of severe systemic illness,
Respiratory Rate ≥ 30 per minute, Heart Rate ≥ 125 beats per
minute, SpO2 ≤ 93% on room air at sea level or PaO2/FIO2 < 300
mm Hg, OR
• Respiratory failure or Acute Respiratory Distress Syndrome
(ARDS), (defined as needing high-flow oxygen, non-invasive or
mechanical ventilation, or ECMO), evidence of shock (systolic blood
pressure < 90 mmHg, diastolic BP < 60 mmHg or requiring
vasopressors), OR
• Significant acute renal, hepatic or neurologic dysfunction,
OR
• Admission to an intensive care unit or death. The secondary
case definition of COVID-19 is defined as the following systemic
symptoms: fever (temperature ≥ 38ºC) or chills, cough, shortness of
breath or difficulty breathing, fatigue, muscle aches or body
aches, headache, new loss of taste or smell, sore throat, nasal
congestion or rhinorrhea, nausea or vomiting or diarrhea AND a
positive NP swab, nasal swab, or saliva sample (or respiratory
sample, if hospitalized) for SARS-CoV-2 by RT-PCR. Death attributed
to COVID-19 is defined as any participant who dies during the study
with a cause directly attributed to a complication of COVID-19.
Asymptomatic SARS-CoV-2 infection is determined by seroconversion
due to infection assessed by bAb levels against SARS-CoV-2 as
measured by a ligand-binding assay specific to the SARS-CoV-2
nucleocapsid protein and a negative NP swab sample for SARS-CoV-2
at Day 1.
Immunogenicity
Assessments: Immunogenicity assessments will include the
following:
• Serum bAb levels against SARS-CoV-2 as measured by
ligand-binding assay specific to the SARS-CoV-2 S protein.
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• Serum bAb levels against SARS-CoV-2 as measured by
ligand-binding assay specific to the SARS-CoV-2 nucleocapsid
protein.
• Serum nAb titer against SARS-CoV-2 as measured by pseudovirus
and/or live virus neutralization assays.
Safety
Assessments: Safety assessments will include monitoring and
recording of the following for each participant:
• Solicited local and systemic ARs that occur during the 7 days
following each injection (ie, the day of injection and 6 subsequent
days). Solicited ARs will be recorded daily using eDiaries.
• Unsolicited AEs observed or reported during the 28 days
following each injection (ie, the day of injection and 27
subsequent days).
• AEs leading to discontinuation from dosing and/or study
participation from Day 1 through Day 759 or withdrawal from the
study.
• MAAEs from Day 1 through Day 759 or withdrawal from the
study.
• SAEs from Day 1 through Day 759 or withdrawal from the
study.
• Abnormal vital sign measurements.
• Physical examination findings.
• Pregnancy and accompanying outcomes.
Investigational
Product, Dosage,
and Route of
Administration:
The mRNA-1273 IP is an LNP dispersion of an mRNA encoding the
prefusion stabilized S protein of SARS-CoV-2 formulated in LNPs
composed of 4 lipids (1 proprietary and 3 commercially available):
the proprietary ionizable lipid SM-102; cholesterol;
1,2-distearoyl-sn-glycero-3 phosphocholine (DSPC); and 1
monomethoxypolyethyleneglycol-2,3-dimyristylglycerol with
polyethylene glycol of average molecular weight 2000 (PEG2000-DMG).
The mRNA-1273 is provided as a sterile liquid for injection and is
a white to off- white dispersion in appearance, at a concentration
of 0.2 mg/mL in 20 mM Tris buffer containing 87 mg/mL sucrose and
10.7 mM sodium acetate at pH 7.5. The placebo is 0.9% sodium
chloride (normal saline) injection, which meets the criteria of the
United States Pharmacopeia (USP). Investigational product will be
administered as an IM injection into the deltoid muscle on a 2-dose
injection schedule on Day 1 and Day 29. Each injection will have a
volume of 0.5 mL and contain
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mRNA-1273 100 µg, or saline placebo. Preferably, vaccine should
be administered into the nondominant arm. The second dose of IP
should be administered in the same arm as the first dose. Unblinded
personnel, who will not participate in any other aspect of the
study, will perform IP accountability, dose preparation, and IP
administration.
Sample Size: The sample size is driven by the total number of
cases to demonstrate VE (mRNA-1273 vs. placebo) to prevent
COVID-19. Under the assumption of proportional hazards over time
and with 1:1 randomization of mRNA-1273 and placebo, a total of 151
COVID-19 cases will provide 90% power to detect a 60% reduction in
hazard rate (60% VE), rejecting the null hypothesis H0: VE ≤ 30%,
with 2 IAs at 35% and 70% of the target total number of cases using
a 1-sided O’Brien-Fleming boundary for efficacy and a log-rank test
statistic with a 1-sided false positive error rate of 0.025. The
total number of cases pertains to the Per-Protocol (PP) Set
accruing at least 14 days after the second dose. There are 2
planned IAs in this study, which will be performed when
approximately 35% and 70% of the target total number of cases have
been observed. Approximately 30,000 participants will be randomized
with the following assumptions:
• The target VE against COVID-19 is 60% (with 95% confidence
interval lower bound ruling out 30%, rejecting the null hypothesis
H0: VE ≤ 30%).
• A 6-month COVID-19 incidence rate of 0.75% in the placebo
arm.
• An annual dropout rate of 2% (loss of evaluable
participants).
• Two IAs at 35% and 70% of total target cases across the 2
treatment groups with O’Brien-Fleming boundaries for efficacy
monitoring.
• 3-month uniform accrual.
• Approximately 15% of participants will be excluded from the PP
population, and participants are at risk for COVID-19 starting 14
days after the second dose.
Power for Selected Secondary Efficacy Endpoints:
For the secondary objective on VE against virologically
confirmed SARS‑CoV‑2 infection or COVID‑19 regardless of
symptomology or severity (COV-INF), the study will have ≥ 90% power
to demonstrate the VE is above 30% (to reject null hypothesis VE ≤
30%) at 1-sided alpha of 2.5% if the true VE to prevent
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COV-INF is 60%, because every COVID-19 endpoint is necessarily a
COV-INF endpoint. For the secondary objective on VE against severe
COVID-19, the power of demonstrating VE based on a total of 20 and
30 events under different scenarios of true VE and VE criteria has
been calculated.
Statistical
Methods:
Statistical Hypotheses: For the primary efficacy objective, the
null hypothesis of this study is that the VE of mRNA-1273 to
prevent first occurrence of COVID-19 is ≤ 30% (ie, H0efficacy: VE ≤
0.3). The study will be considered to meet the primary efficacy
objective if the corresponding CI of VE rules out 30% at either one
of the interim analyses or at the primary analysis. In the primary
analysis of VE of COVID-19, cases will be counted starting 14 days
after the second dose of IP. Vaccine efficacy is defined as the
percent reduction in the hazard of the primary endpoint (mRNA-1273
vs placebo). Equivalently, the null hypothesis is:
• H0efficacy: hazard ratio (HR) ≥ 0.7 (equivalently,
proportional hazards VE ≤ 0.3).
A stratified Cox proportional hazard model will be used to
assess the magnitude of the treatment group difference (ie, HR)
between mRNA-1273 and placebo at a 1-sided 0.025 significance
level. Analysis Populations: Analysis populations for statistical
analyses are Randomization Set, Full Analysis Set (FAS), Modified
Intent-to-Treat (mITT) Set, PP Set, Immunogenicity Subset,
Solicited Safety Set, and Safety Set, as shown in the table
below:
Population Description
Randomization Set All participants who are randomized,
regardless of the participants’ treatment status in the study.
Full Analysis Set (FAS)
All randomized participants who received at least one dose of
IP. Participants will be analyzed according to the group to which
they were randomized.
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Modified Intent--to-Treat (mITT) Set
All participants in the FAS who had no immunologic or virologic
evidence of prior COVID-19 (ie, negative NP swab test at Day 1
and/or bAb against SARS-CoV-2 nucleocapsid below limit of detection
[LOD] or lower limit of quantification [LLOQ]) at Day 1 before the
first dose of IP. Participants will be analyzed according to the
group to which they were randomized.
Per-protocol (PP) Set
All participants in the mITT Set who received planned doses of
IP per schedule and have no major protocol deviations, as
determined and documented by Sponsor prior to DBL and unblinding,
that impact critical or key study data. Participants will be
analyzed according to the group to which they were randomized.
Immunogenicity Subset
All participants in the FAS who had a valid immunogenicity test
result prior to the first dose of IP and at least 1 valid result
after the first dose of IP.
Solicited Safety Set
The Solicited Safety Set consists of all randomized participants
who received at least one dose of IP and contributed any solicited
AR data. The Solicited Safety Set will be used for the analyses of
solicited ARs and participants will be included in the treatment
group corresponding to the IP that they actually received.
Safety Set All randomized participants who received at least one
dose of IP. The Safety Set will be used for all analyses of safety
except for the solicited ARs. Participants will be included in the
treatment group corresponding to the IP that they actually
received.
Efficacy Analyses: Efficacy analyses will be performed using the
FAS, mITT and PP populations, and participants will be included in
the treatment group to which they are randomized. The primary
analysis population for efficacy will be the PP Set.
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The Table below summarizes the analysis approach for primary and
secondary efficacy endpoints. Sensitivity analysis methods are
described for each endpoint as applicable.
Endpoint Statistical Analysis Methods
Primary endpoint:
Vaccine efficacy (VE) of mRNA-1273 to prevent COVID-19
• Primary analysis: VE will be estimated with 1 - HR (mRNA-1273
vs placebo) using a Cox proportional hazard regression model with
treatment group as a fixed effect and adjust for stratification
factor based on the PP Set, with cases counted starting 14 days
after the second dose of IP.
• Analysis using the same model based on the mITT Set.
• Sensitivity analysis using the same model based on the PP Set,
with cases counted starting either immediately after the second
dose of IP or immediately after the first dose of IP.
• Subgroup analysis of the primary efficacy endpoint will be
performed to assess consistency of VE, such as in the age groups ≥
18 and < 65 years and ≥ 65 years.
• Supportive analysis of VE to be estimated with 1 - ratio of
incidence rates with 95% confidence interval (CI) using the exact
method conditional upon the total number of cases.
• Supportive analysis of cumulative incidence VE.
Secondary endpoints:
• Vaccine efficacy of mRNA-1273 to prevent severe COVID-19
• Vaccine efficacy of mRNA-1273 to prevent serologically
Similar analysis method as for the primary endpoint analysis.
For each of the secondary endpoints:
• Primary analysis: VE will be estimated with 1 - HR (mRNA-1273
vs placebo) using a Cox proportional hazard regression model with
treatment
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confirmed SARS‑CoV‑2 infection or COVID‑19 regardless of
symptomatology or severity.
• Vaccine efficacy of mRNA-1273 to prevent COVID-19 using a
secondary definition of symptoms
• Vaccine efficacy of mRNA-1273 to prevent death caused by
COVID-19
• Vaccine efficacy of mRNA-1273 to prevent COVID-19 after the
first dose of IP
• Vaccine efficacy of mRNA-1273 to prevent asymptomatic
SARS-CoV-2 infection
group as a fixed effect and adjusting for stratification factor
based on the PP Set, with cases counted starting 14 days after the
second dose of IP.
• Analysis using the same model based on the mITT Set.
• Sensitivity analyses with cases counted starting immediately
after the second dose of IP, 14 days after the first dose of IP,
immediately after the first dose of IP, and immediately after
randomization.
• Vaccine efficacy and 95% CI based on the case incidence will
be estimated with 1 - ratio of incidence rates using the exact
method conditional upon the total number of cases.
Vaccine efficacy of mRNA-1273 to prevent COVID-19 in all study
participants, regardless of evidence of prior SARS-CoV-2
infection
The FAS population will be used for this secondary objective,
using similar analysis methods as for the primary endpoint
analysis.
• Primary analysis: VE will be estimated with 1 - HR (mRNA-1273
vs placebo) using a Cox proportional hazard regression model with
treatment group as a fixed effect and adjusting for stratification
factor based on the FAS, with cases counted starting 14 days after
the second dose of IP.
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• Sensitivity analyses with cases counted starting immediately
after the second dose of IP, 14 days after the first dose of IP,
immediately after the first dose of IP, and immediately after
randomization.
Safety: Safety and reactogenicity will be assessed by clinical
review of all relevant parameters including solicited ARs (local
and systemic events), unsolicited AEs, SAEs, MAAEs, AEs leading to
discontinuation, abnormal vital signs, and physical examination
findings. All safety analyses will be based on the Safety Set,
except summaries of solicited ARs, which will be based on the
Solicited Safety Set. All safety analyses will be provided by
treatment group unless otherwise specified. The number and
percentage of participants with any solicited local AR, with any
solicited systemic AR, and with any solicited AR during the 7-day
follow-up period after each injection will be provided. A 2-sided
95% exact CI using the Clopper-Pearson method will be also provided
for the percentage of participants with any solicited AR for each
treatment group. The number and percentage of participants with
solicited ARs, unsolicited AEs, SAEs, MAAEs, Grade 3 or higher ARs
and AEs, and AEs leading to discontinuation from study vaccine or
participation in the study will be summarized. Unsolicited AE will
be presented by MedDRA preferred term and system organ class. For
all other safety parameters, descriptive summary statistics will be
provided. Further details will be described in the statistical
analysis plan (SAP). Immunogenicity: The secondary immunogenicity
endpoints will be analyzed using the Immunogenicity Subset, by
treatment group and by baseline SARS-CoV-2 serostatus, unless
otherwise specified. The SAP will describe the complete set of
immunogenicity analyses, including the approach to sample
individuals into an Immunogenicity Subset for characterizing
vaccine immunogenicity and assessing immunological correlates of
risk and protection. Data from quantitative immunogenicity assays
will be summarized for each treatment group using positive response
rates and geometric means with 95% confidence intervals, for each
timepoint for which
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an assessment is performed. Data from qualitative (ie, yielding
a positive or negative result) assays will be summarized by
tabulating the frequency of positive responses for each assay by
group at each timepoint that an assessment is performed. Analyses
will focus on the 2 key immunogenicity time points and the change
in marker response between them: Day 1 before the first dose of IP
and Day 57 (28 days after the second dose of IP). The SAP will
describe the complete set of immunogenicity analyses. Quantitative
levels or geometric mean titer (GMT) of specific bAb with
corresponding 95% CI at each timepoint and geometric mean fold rise
(GMFR) of specific bAb with corresponding 95% CI at each
post-baseline timepoint over pre-dose baseline at Day 1 will be
provided by study arm. Descriptive summary statistics including
median, minimum, and maximum will also be provided. GMT of specific
nAb with corresponding 95% CI at each timepoint and GMFR of
specific nAb with corresponding 95% CI at each post-baseline
timepoint over pre-dose baseline at Day 1 will be provided by study
arm. Descriptive summary statistics including median, minimum, and
maximum will also be provided. For summarizations of group
variables values, antibody values reported as below the LOD or LLOQ
will be replaced by 0.5 × LOD or 0.5 × LLOQ. Values that are
greater than the upper limit of quantification (ULOQ) will be
converted to the ULOQ. The number and percentage of participants
with a fold rise ≥ 2, ≥ 3, and ≥ 4 of serum SARS-CoV-2-specific nAb
titers and participants with seroconversion due to vaccination from
baseline will be provided with 2-sided 95% CI using the
Clopper-Pearson method at each post-baseline timepoint.
Seroconversion due to vaccination at a participant level is defined
as a change from below the LOD or LLOQ to equal or above LOD or
LLOQ, or at least a 4-fold rise in terms of neutralizing antibody
or vaccine antigen-specific binding antibody in participants with
pre-existing bAb or nAb. The GMT of specific nAb for each group and
the geometric mean ratio (GMR) of mRNA-1273 versus placebo with
corresponding 2-sided 95% CI will be estimated at each study
timepoint using an analysis of covariance (ANCOVA) model with the
treatment group and baseline values, if applicable, as explanatory
variables, the analysis may adjust for the stratification
factor.
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1.2. Schema Figure 1: Study Flow Diagram
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TABLE OF CONTENTS
Clinical study Protocol
...........................................................................................................
1 Protocol Approval – Sponsor Signatory
................................................................................
2 Declaration of Investigator
....................................................................................................
3 Protocol Amendment Summary of Changes
..........................................................................
4 IRB and Regulatory Authority Approval
...............................................................................
5 1. Protocol Summary
...................................................................................................
6 1.1. Synopsis
..................................................................................................................
6 1.2. Schema
..................................................................................................................
20 Table of Contents
................................................................................................................
21 List of Tables
................................................................................................................
25 List of Figures
................................................................................................................
25 List of Abbreviations
...........................................................................................................
26 2. Introduction
...........................................................................................................
29 2.1. Study Rationale
.....................................................................................................
29 2.2. Background and Overview
....................................................................................
29
2.2.1. Nonclinical Studies
........................................................................................
30 2.2.2. Clinical Studies
..............................................................................................
30
2.3. Benefit/Risk Assessment
.......................................................................................
31 2.3.1. Potential Benefits of Study Participation
....................................................... 31 2.3.2.
Risks from Study Participation
......................................................................
32 2.3.3. Overall Benefit/Risk Conclusion
...................................................................
33
3. Objectives and endpoints
.......................................................................................
34 4. Study Design
.........................................................................................................
38 4.1. General Design
......................................................................................................
38 4.2. Scientific Rationale for Study Design
...................................................................
41 4.3. Choice of Dose and Control Product
....................................................................
42 4.4. End of Study Definition
........................................................................................
42 5. Study Population
...................................................................................................
43 5.1. Inclusion Criteria
...................................................................................................
43 5.2. Exclusion Criteria
..................................................................................................
44 5.3. Participant Restrictions
.........................................................................................
45 5.4. Screen Failures
......................................................................................................
45 6. Study Treatment
....................................................................................................
47 6.1. Investigational Product
..........................................................................................
47
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6.2. Dosing and Management of Investigational Product
............................................ 47 6.2.1. Method of
Randomly Assigning Participants to Treatment Groups ..............
47 6.2.2. Administration of Investigational Product
..................................................... 48 6.2.3.
Delivery and Receipt
.....................................................................................
49 6.2.4. Packaging and Labeling
.................................................................................
49 6.2.5. Storage
...........................................................................................................
50 6.2.6. Investigational Product Accountability
......................................................... 50 6.2.7.
Handling and Disposal
...................................................................................
50 6.2.8. Unblinding
.....................................................................................................
51
6.3. Study Treatment Compliance
................................................................................
52 6.4. Prior and Concomitant Therapy
............................................................................
53
6.4.1. Prior Medications and Therapies
....................................................................
53 6.4.2. Concomitant Medications and Therapies
....................................................... 53 6.4.3.
Concomitant Medications and Vaccines that May Lead to the
Elimination of a Participant from Per-Protocol Analyses
............................................................................
54
7. Delaying or Discontinuing Study Treatment and Participant
Withdrawal from the Study
......................................................................................................
55
7.1. Criteria for Delay of Study Treatment
..................................................................
55 7.2. Discontinuation of Study Treatment
.....................................................................
55 7.3. Participant Withdrawal from the Study
.................................................................
57
7.3.1. Participant Withdrawal
..................................................................................
57 7.4. Lost to Follow-up
..................................................................................................
58 8. Study Assessments and Procedures
.......................................................................
59 8.1. Efficacy and Immunogenicity Assessments and Procedures
................................ 60
8.1.1. Efficacy Assessments Related to COVID-19 and SARS-CoV-2
Infection ... 60 8.1.2. Surveillance for COVID-19 Symptoms
......................................................... 61 8.1.3.
Convalescent Period Starting with the Illness Visit
....................................... 64 8.1.4. Ancillary
Supplies for Participant Use
.......................................................... 66
8.1.5. Immunogenicity Assessments
........................................................................
66
8.2. Safety Assessments
...............................................................................................
67 8.2.1. Safety Phone Calls
.........................................................................................
68 8.2.2. Use of Electronic Diaries
...............................................................................
68 8.2.3. Demographics/Medical History
.....................................................................
70 8.2.4. Physical Examination
....................................................................................
70
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8.2.5. Vital Sign Measurements
...............................................................................
71 8.2.6. Blood Sampling Volumes
..............................................................................
71
8.3. Safety Definitions and Procedures
........................................................................
72 8.3.1. Adverse Event
................................................................................................
72 8.3.2. Medically Attended Adverse Events
............................................................. 73
8.3.3. Serious Adverse Events
.................................................................................
73 8.3.4. Solicited Adverse Reactions
..........................................................................
74 8.3.5. Recording and Follow-up of Pregnancy
........................................................ 76 8.3.6.
Recording and Follow-up of an AE and/or SAE
........................................... 77 8.3.7. Time Period
and Frequency for Collecting AE and SAE Information .......... 77
8.3.8. Assessment of Intensity
.................................................................................
78 8.3.9. Assessment of Causality
................................................................................
78 8.3.10. Reporting Adverse Events
.............................................................................
79 8.3.11. Regulatory Reporting Requirements for SAEs
.............................................. 80
8.4. Monitoring Committees
........................................................................................
80 8.4.1. Protocol Safety Review Team
.......................................................................
80 8.4.2. Data and Safety Monitoring Board
................................................................ 80
8.4.3. Adjudication Committee
................................................................................
82
8.5. Management of Overdose
.....................................................................................
82 8.6. Pharmacokinetics
..................................................................................................
82 8.7. Pharmacodynamics
...............................................................................................
82 8.8. Exploratory Assessments and Biomarkers
............................................................ 82
8.9. Medical Resource Utilization and Health
Economics........................................... 82 9.
Statistical Considerations
......................................................................................
83 9.1. Blinding and Responsibility for Analyses
............................................................. 83
9.2. Statistical Hypotheses
...........................................................................................
83 9.3. Sample Size Determination
...................................................................................
84
9.3.1. Power for Selected Secondary Efficacy Endpoints
....................................... 86 9.4. Analysis
Populations
.............................................................................................
87 9.5. Statistical Analyses
...............................................................................................
88
9.5.1. Efficacy Analyses
..........................................................................................
89 9.5.2. Safety Analyses
..............................................................................................
92 9.5.3. Immunogenicity Analyses
.............................................................................
94 9.5.4. Exploratory Analyses
.....................................................................................
96
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9.5.5. Subgroup Analyses
........................................................................................
97 9.6. Interim Analyses
...................................................................................................
97 10. References
.............................................................................................................
99 11. Supporting Documentation and Operational Considerations
.............................. 102 11.1. APPENDIX 1: Schedules of
Events
...................................................................
103 11.2. APPENDIX 2: Study Governance Considerations
............................................. 116
11.2.1. Regulatory and Ethical Considerations
........................................................ 116
11.2.2. Study Monitoring
.........................................................................................
116 11.2.3. Audits and Inspections
.................................................................................
118 11.2.4. Financial Disclosure
....................................................................................
118 11.2.5. Recruitment Procedures
...............................................................................
118 11.2.6. Informed Consent Process
...........................................................................
119 11.2.7. Protocol Amendments
..................................................................................
120 11.2.8. Protocol Deviations
......................................................................................
120 11.2.9. Data Protection
............................................................................................
120 11.2.10. Sample Retention and Future Biomedical Research
.................................... 121 11.2.11. Data Quality
Assurance and Quality Control
.............................................. 122 11.2.12. Data
Collection and Management
................................................................
123 11.2.13. Source Documents
.......................................................................................
123 11.2.14. Retention of Records
...................................................................................
124 11.2.15. Study and Site Closure
.................................................................................
124 11.2.16. Publication Policy
........................................................................................
125
11.3. APPENDIX 3: Contraceptive Guidance
............................................................. 126
11.4. APPENDIX 4 - Statistical Appendices
...............................................................
128
11.4.1. Estimands and Estimand Specifications
...................................................... 128 11.4.2.
Statistical Methods and Sensitivity Analyses
.............................................. 131
11.5. APPENDIX 5: Protocol Amendment History
..................................................... 132
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LIST OF TABLES
Table 1: Objectives and Endpoints
..............................................................................
34 Table 2: Summary of Treatment Groups
.....................................................................
47 Table 3: Grading of COVID-19 Symptoms
................................................................ 65
Table 4: Maximum Planned Blood Sampling Volumes per Participant by
Visit ........ 72 Table 5: Solicited Adverse Reactions and Grades
...................................................... 75 Table 6:
Conditions and Sample Size to Demonstrate Vaccine Efficacy
.................... 85 Table 7: Power of Demonstrating Vaccine
Efficacy Against Severe COVID-19 ....... 87 Table 8: Populations
for Analyses
...............................................................................
88 Table 9: Statistical Analysis Methods of Efficacy Endpoints
..................................... 89 Table 10: Analysis
Strategy for Safety Parameters
....................................................... 93 Table
11: Immunogenicity Endpoints and Statistical Methods
..................................... 96 Table 12: Burden of
Disease Score
...............................................................................
96 Table 13: Interim Boundaries Using O’Brien-Fleming Spending
function, Calculation
Based on the PP Set for the Primary Efficacy Endpoint
............................... 98 Table 14: Schedule of Events
(Vaccination Phase, Day 1 – Day 57) ......................... 104
Table 15: Schedule of Events (Surveillance Phase, Day 64 – Day 394)
..................... 108 Table 16: Schedule of Events
(Surveillance Phase, Day 401 – Day 759) ................... 112
Table 17: Schedule of Events (Convalescent Period, Starting with
the Illness Visit) . 114 Table 18: Intercurrent Event Types
.............................................................................
128 Table 19: Primary Objective and Estimands with Rationale for
Strategies to Address
Intercurrent Events for Per-Protocol Analysis
............................................ 129 Table 20: Summary
of Statistical Methods and Sensitivity Analyses
......................... 131
LIST OF FIGURES
Figure 1: Study Flow Diagram
.....................................................................................
20 Figure 2: Event/Case-Driven Study with 24 Months of Planned
Follow-Up ............... 39 Figure 3: Surveillance for COVID-19
Symptoms and the Corresponding Clinical Data
Pathways
........................................................................................................
63 Figure 4: Boundary Crossing Probabilities by Effect Size
........................................... 85
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LIST OF ABBREVIATIONS
The following abbreviations and terms are used in this study
protocol.
Abbreviation Definition
AC Adjudication Committee AE adverse event AR adverse reaction
ARDS acute respiratory distress syndrome bAb binding antibody BARDA
Biomedical Advance Research and Development Authority BOD burden of
disease BUN blood urea nitrogen CDC US Centers for Disease Control
and Prevention CFR Code of Federal Regulations CI confidence
interval CMV cytomegalovirus CONSORT Consolidated Standards of
Reporting Trials CoV coronavirus COV-INF virologically confirmed
SARS-CoV-2 infection regardless of
symptomology or severity CRO contract research organization CSR
clinical study report DHHS Department of Health and Human Services
DMID Division of Microbiology and Infectious Diseases DSMB Data and
Safety Monitoring Board DSPC
1,2-distearoyl-sn-glycero-3-phosphocholine eCRF electronic case
report form eDiary electronic diary ART antiretroviral therapy FAS
full analysis set FDA Food and Drug Administration FSH
follicle-stimulating hormone GCP Good Clinical Practice GMFR
geometric mean fold rise GMP Good Manufacturing Practice GMT
geometric mean titer
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Abbreviation Definition
HCP healthcare practitioner HIV hMPV
Human Immunodeficiency Virus human metapneumovirus
HR hazard ratio HRT hormonal replacement therapy IA interim
analysis IB investigator’s brochure ICF informed consent form ICH
International Council for Harmonisation IM intramuscular IP
investigational product IRB institutional review board IRT
interactive response technology LB lower boundary LLOQ lower limit
of quantification LNP lipid nanoparticle LOD limit of detection
MAAE medically attended adverse event MedDRA Medical Dictionary for
Regulatory Activities MERS-CoV Middle East Respiratory Syndrome
coronavirus mRNA messenger RNA nAb neutralizing antibody NIAID
National Institute of Allergy and Infectious Diseases NP
nasopharyngeal PCR polymerase chain reaction PEG2000-DMG
1-monomethoxypolyethyleneglycol-2,3-dimyristylglycerol with
polyethylene glycol of average molecular weight 2000 PIV3
parainfluenza virus type 3 PP per-protocol RT-PCR reverse
transcriptase polymerase chain reaction S spike S-2P spike protein
with 2 proline residues introduced for stability in a
prefusion conformation SAE serious adverse event SAP statistical
analysis plan
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Abbreviation Definition
SARS-CoV Severe Acute Respiratory Syndrome coronavirus SM-102
heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy)
hexyl)
amino) octanoate SoE Schedule of Events TEAE treatment-emergent
adverse event ULOQ upper limit of quantification USP United States
Pharmacopeia VE vaccine efficacy WHO World Health Organization
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2. INTRODUCTION
2.1. Study Rationale Coronaviruses (CoVs) are a large family of
viruses that cause illness ranging from the common cold to more
severe diseases, such as Middle East Respiratory Syndrome
(MERS-CoV) and Severe Acute Respiratory Syndrome (SARS-CoV).
An outbreak of the CoV disease (COVID-19) caused by SARS-CoV-2
began in Wuhan, Hubei Province, China in December 2019 and has
spread throughout China and to over 216 other countries and
territories, including the United States (WHO 2020). On 11 March
2020, the World Health Organization (WHO) officially declared
COVID-19 a pandemic. As of 28 May 2020, the WHO reported more than
5,593,631 confirmed cases and 353,334 deaths globally and the US
Centers for Disease Control and Prevention (CDC) reported 1,698,523
confirmed and probable cases of COVID-19, with 100,446 deaths in
the United States (CDC 2020a). The CDC have reported that the
highest risk of disease burden is in older adults (≥ 65 years old)
and people of any age who have serious underlying medical
conditions, such as chronic lung disease or moderate to severe
asthma; serious heart conditions; severe obesity; diabetes; chronic
kidney disease requiring dialysis; liver disease; and those who are
immunocompromised (CDC 2020b).
There is currently no vaccine against SARS-CoV-2. Global efforts
to evaluate novel antivirals and therapeutic strategies to treat
severe SARS-CoV-2 infections have intensified, but no proven
therapeutic currently exists. Therefore, there is an urgent public
health need for rapid development of novel interventions to prevent
the spread of this disease. The primary goal of this Phase 3 study
is to evaluate the vaccine efficacy (VE) of mRNA-1273 to prevent
COVID-19, compared to placebo.
2.2. Background and Overview ModernaTX, Inc. (the Sponsor) has
developed a rapid-response, proprietary vaccine platform based on a
messenger RNA (mRNA) delivery system. The platform is based on the
principle and observations that cells in vivo can take up mRNA,
translate it, and then express protein viral antigen(s) on the cell
surface. The delivered mRNA does not enter the cellular nucleus or
interact with the genome, is nonreplicating, and is expressed
transiently. mRNA vaccines have been used to induce immune
responses against infectious pathogens such as cytomegalovirus
(CMV) (NCT03382405), human metapneumovirus (hMPV) and parainfluenza
virus type 3 (PIV3) (NCT03392389), Zika virus (NCT03325075), and
influenza virus (NCT03076385 and NCT03345043).
The Sponsor is using its mRNA-based platform to develop a novel
lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine against
SARS-CoV-2 (mRNA-1273). mRNA-1273
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encodes for the full-length spike (S) protein of SARS-CoV-2,
modified to introduce 2 proline residues to stabilize the S protein
(S2P) in a prefusion conformation. The CoV S protein mediates
attachment and entry of the virus into host cells (by fusion),
making it a primary target for neutralizing antibodies that prevent
infection (Johnson et al 2016; Wang et al 2015; Wang et al 2018;
Chen et al 2017; Corti et al 2015; Yu et al 2015; Kim et al 2019;
Widjaja et al 2019). It has been confirmed that the stabilized
SARS-CoV-2 S2P antigen presents in the correct prefusion
conformation (Wrapp et al 2020).
The development of the mRNA-1273 vaccine is being accelerated to
address the current SARS-CoV-2 outbreak as a result of the uniquely
rapid and scalable manufacturing process for mRNA-1273. The primary
goal of this Phase 3 study is to evaluate the VE of mRNA-1273 to
prevent COVID-19, compared to placebo.
2.2.1. Nonclinical Studies Nonclinical studies have demonstrated
that CoV S proteins are immunogenic and S protein-based vaccines,
including those based on mRNA delivery platforms, are protective in
animals. Prior clinical studies of vaccines targeting related CoVs
and other viruses have demonstrated that mRNA-based vaccines are
safe and immunogenic. It is therefore anticipated that mRNA-1273
will generate robust immune responses to the SARS-CoV-2 S protein
and will be well tolerated. In addition, mRNA-1273 has shown
preliminary evidence of protection against SARS-CoV-2 in a murine
model of infection (data on file).
In support of development of mRNA-1273 for prophylaxis against
SARS-CoV-2 infection, nonclinical immunogenicity, biodistribution,
and safety studies have been completed with similar mRNA-based
vaccines formulated in LNPs containing SM-102 (heptadecan-9-yl 8
((2 hydroxyethyl)(6 oxo 6-(undecyloxy)hexyl)amino)octanoate), the
novel proprietary lipid used in the mRNA-1273 LNP formulation.
A detailed review of nonclinical experience with mRNA-1273
vaccine is provided in the investigator’s brochure (IB).
2.2.2. Clinical Studies The mRNA-1273 vaccine is currently being
evaluated for safety and immunogenicity in a dose-ranging Phase 1
study (NCT04283461) sponsored and conducted by the Division of
Microbiology and Infectious Diseases (DMID) of the National
Institute of Allergy and Infectious Diseases (NIAID). The Phase 1
DMID study is an open-label dose-ranging study of mRNA-1273 in
healthy adult male and non-pregnant female participants in 3 age
groups: age 18 to 55 years, inclusive (45 participants); age 56 to
70 years, inclusive (30 participants); and ≥ 71 years (30
participants). Participants in each cohort are randomly assigned to
1 of 3 dose levels of mRNA-1273: 25 μg,
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100 μg, and 250 μg. Each participant will receive an IM
injection (0.5 mL) of mRNA-1273 on Days 1 and 29 in the deltoid
muscle and will be followed for 13 months after the second
injection.
As of 14 May 2020, 15 participants in each of the 3 dose levels
of the 18 to 55-year age cohort had received at least 1 dose of
mRNA-1273. Recruitment of participants in the 2 older-age cohorts
is ongoing. There have been no SAEs reported and no triggering of
study pause rules. A review of preliminary solicited local and
systemic ARs in participants in the 18 to 55-year age cohort after
the second injection showed 3 participants in the 100 µg dose group
who reported severe local ARs (grade 3 erythema and induration) and
3 participants in the 250 µg dose group who reported severe
systemic ARs (fever, fatigue, feverishness, myalgia, and nausea).
These adverse reactions resolved within 24 hours and were not
assessed as serious.
Additionally, a dose-finding Phase 2a study (mRNA-1273-P201)
conducted by the Sponsor under IND 19745 will expand the safety and
immunogenicity database by testing 2 two dose levels (50 µg and 100
µg) in 400 adults.
As of January 6, 2020, approximately 365 participants were dosed
with either an SM-102-containing lipid vaccine or placebo (doses
ranging from 10 to 300 μg) across 3 Phase 1 studies for CMV,
HMPV/PIV3, or Zika vaccines. There were no related serious adverse
events (SAEs), and the vaccines appeared to be generally well
tolerated. The results of 2 Phase 1 dose-ranging studies of an
earlier formulation of the Sponsor’s mRNA vaccine against H10N8 and
H7N9 pandemic influenza was recently published. Both vaccines were
immunogenic and well tolerated at doses up to 100 µg (NCT03076385
and NCT03345043; Feldman et al 2019). A detailed review of clinical
experience with LNPs containing SM-102 (mRNA vaccines and placebo)
is provided in the IB.
2.3. Benefit/Risk Assessment
2.3.1. Potential Benefits of Study Participation The target
study population for this study is adults with no known history of
SARS-CoV-2 infection but whose locations or circumstances put them
at high risk of COVID-19. The following benefits may accrue to
participants:
• The mRNA-1273 vaccine may be an effective vaccine against
COVID-19.
• A baseline (Day 1) evaluation for SARS-CoV-2 infection and
ongoing surveillance for COVID-19 throughout the study.
• Contributing to the development of a vaccine against COVID-19,
a current pandemic disease.
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2.3.2. Risks from Study Participation Immediate systemic
allergic reactions (eg, anaphylaxis) can occur following any
vaccination. These reactions are very rare and are estimated to
occur once per 450,000 vaccinations for vaccines that do not
contain allergens such as gelatin or egg protein (Zent et al 2002).
As a precaution, all participants will remain under observation at
the study site for at least 30 minutes after vaccination.
Vasovagal syncope (fainting) can occur before or after any
vaccination, is usually triggered by the pain or anxiety caused by
the injection and is not related to the substance injected.
Therefore, it is important that standard precautions and procedures
be followed to avoid injury from fainting.
Intramuscular injection with other mRNA vaccines manufactured by
the Sponsor containing the SM-102 lipid formulation commonly
results in a transient and self-limiting local inflammatory
reaction. This typically includes pain, erythema (redness), or
swelling (hardness) at the injection site, which are mostly
mild-to-moderate in severity and usually occur within 24 hours of
vaccination. More severe, but self-limited, local reactions,
erythema and induration, have been observed at dose of mRNA-1273
exceeding the dose proposed in this study.
Most systemic adverse events observed after vaccination do not
exceed mild-to-moderate severity. The most commonly reported
systemic adverse reactions (ARs) are anticipated to be fever,
fatigue, chills, headache, myalgias and arthralgias. More severe
reactions, including erythema, induration, fever, headache and
nausea, were reported after receiving doses of mRNA-1273 that were
greater than the dose proposed for use in this study. In all cases,
the reactions resolved spontaneously.
Laboratory abnormalities (including increases in liver
functional tests and serum lipase levels) following vaccination
were observed in clinical studies with similar mRNA-based vaccines.
These abnormalities were without clinical symptoms or signs and
returned toward baseline (Day 1) values over time. The clinical
significance of these observations is unknown. Further details are
provided in the current IB.
There is a theoretical risk that active vaccination to prevent
the novel viral infection caused by SARS-CoV-2 may cause a
paradoxical increase in the risk of disease. This possibility is
based on the rare phenomenon of vaccine-associated disease
enhancement which was first seen in the 1960s with 2 vaccines made
in the same way (formalin-inactivated whole virus) and designed to
protect children against infection with RSV (Chin et al 1969) or
measles (Fulginiti et al 1967). Disease enhancement has also been
proposed as a possible explanation for cases of more serious
disease associated with dengue vaccination (Thomas and Yoon 2019;
WHO 2018). It is not known if mRNA-1273 will increase the risk of
enhanced disease.
To monitor the risk of enhanced disease in this study, an
independent Data and Safety Monitoring Board (DSMB) will review
unblinded cases of COVID-19 to assess for inefficacy and also
for
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numerical imbalance in cases of both COVID-19 and severe
COVID-19 with the purpose of providing a non-binding recommendation
to the Sponsor (Section 8.4.2).
2.3.3. Overall Benefit/Risk Conclusion All participants will be
included based on their increased risk of SARS-CoV-2 infection.
Accordingly, all will benefit from baseline and ongoing evaluations
for SARS-CoV-2 infection.
Since this is a placebo-controlled study (Section 4), half the
participants will have the potential to receive mRNA-1273 vaccine,
the efficacy of which is unknown at present. Vaccination with
mRNA-1273 may not prevent COVID-19 in all vaccinees.
Participants who receive placebo as part of this study may have
an opportunity cost of not being treated with another
investigational vaccine against COVID-19.
The placebo for this study is a saline solution, without any
LNP. Thus, participants receiving saline may be at lower risk of
adverse events (AEs) related to injection than participants
receiving mRNA-1273.
Safety findings will be monitored and periodically reviewed by
the DSMB to evaluate the safety and treatment status of all
participants. The DSMB will review and assess the safety data as
described in Section 8.4.2.
Considering the lack of approved vaccines for COVID-19, the
participants’ risk of COVID-19 outside the study, and the
nonclinical and clinical data to date, the Sponsor considers the
potential benefits of participation to exceed the risks.
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3. OBJECTIVES AND ENDPOINTS Table 1: Objectives and
Endpoints
Objectives and Endpoints
Primary Objective Primary Endpoints
Efficacy Objective
(Primary):
To demonstrate the efficacy of mRNA-1273 to prevent
COVID-19.
Efficacy Endpoints (Primary): Vaccine efficacy of mRNA-1273 to
prevent the first occurrence of COVID-19 starting 14 days after the
second dose of investigational product (IP), where COVID-19 is
defined as symptomatic disease based on the following criteria:
• The participant must have experienced at least TWO of the
following systemic symptoms: Fever (≥ 38ºC), chills, myalgia,
headache, sore throat, new olfactory and taste disorder(s), OR
• The participant must have experienced at least ONE of the
following respiratory signs/symptoms: cough, shortness of breath or
difficulty breathing, OR clinical or radiographical evidence of
pneumonia; AND
• The participant must have at least one NP swab, nasal swab, or
saliva sample (or respiratory sample, if hospitalized) positive for
SARS-CoV-2 by RT-PCR.
Safety Objective (Primary):
To evaluate the safety and reactogenicity of 2 injections of the
mRNA-1273 vaccine given 28 days apart.
Safety Endpoint (Primary):
• Solicited local and systemic ARs through 7 days after each
dose of IP.
• Unsolicited AEs through 28 days after each dose of IP.
• Medically attended adverse events (MAAEs) or AEs leading to
withdrawal through the entire study period.
• SAEs throughout the entire study period.
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Efficacy Objectives
(Secondary) Efficacy Endpoints (Secondary)
To evaluate the efficacy of mRNA-1273 to prevent severe
COVID-19.
• Vaccine efficacy of mRNA-1273 to prevent severe COVID-19,
defined as first occurrence of COVID-19 starting 14 days after the
second dose of IP, (as per the primary endpoint) AND any of the
following:
o Clinical signs indicative of severe systemic illness,
Respiratory Rate ≥ 30 per minute, Heart Rate ≥ 125 beats per
minute, SpO2 ≤ 93% on room air at sea level or PaO2/FIO2 < 300
mm Hg, OR
o Respiratory failure or Acute Respiratory Distress Syndrome
(ARDS), (defined as needing high-flow oxygen, non-invasive or
mechanical ventilation, or ECMO), evidence of shock (systolic blood
pressure < 90 mmHg, diastolic BP < 60 mmHg or requiring
vasopressors), OR
o Significant acute renal, hepatic or neurologic dysfunction,
OR
o Admission to an intensive care unit or death. To evaluate the
efficacy of mRNA-1273 to prevent serologically confirmed SARS-CoV-2
infection or COVID-19 regardless of symptomatology or severity.
Vaccine efficacy of mRNA-1273 to prevent the first occurrence of
either COVID-19 or SARS-CoV-2 infection starting 14 days after the
second IP dose. This endpoint is a combination of COVID-19, defined
as for the primary endpoint, and asymptomatic SARS-CoV-2 infection,
determined by seroconversion assessed by bAb levels against
SARS-CoV-2 as measured by a ligand-binding assay specific to the
SARS-CoV-2 nucleocapsid protein and with a negative nasopharyngeal
(NP) swab sample for SARS-CoV-2 at Day 1 (Section 8.1.1).
To evaluate VE against a secondary definition of COVID-19.
Vaccine efficacy of mRNA-1273 to prevent the secondary case
definition of COVID-19 starting 14 days after the second IP dose.
The secondary case definition of COVID-19 is defined as the
following systemic symptoms: fever (temperature ≥ 38ºC), or chills,
cough, shortness of breath or difficulty breathing, fatigue, muscle
aches or body aches, headache, new loss of taste or smell, sore
throat, nasal congestion or rhinorrhea, nausea or vomiting, or
diarrhea AND a positive NP swab, nasal swab, or saliva sample (or
respiratory sample, if hospitalized) for SARS-CoV-2 by RT-PCR.
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To evaluate VE to prevent death caused by COVID-19.
Vaccine efficacy of mRNA-1273 to prevent death due to a cause
directly attributed to a complication of COVID-19, starting 14 days
after the second IP dose.
To evaluate the efficacy of mRNA-1273 to prevent COVID-19 after
the first dose of IP.
Vaccine efficacy of mRNA-1273 to prevent the first occurrence of
COVID-19 starting 14 days after the first dose of IP.
To evaluate the efficacy of mRNA-1273 to prevent COVID-19 in all
study participants, regardless of evidence of prior SARS-CoV-2
infection.
Vaccine efficacy of mRNA-1273 to prevent the first occurrence of
COVID-19 starting 14 days after the second dose of IP regardless of
evidence of prior SARS-CoV-2 infection determined by serologic
titer against SARS-CoV-2 nucleocapsid (FAS analysis population, see
Section 9.4).
To evaluate the efficacy of mRNA-1273 to prevent asymptomatic
SARS-CoV-2 infection.
Vaccine efficacy to prevent the first occurrence of SARS-CoV-2
infection in the absence of symptoms defining COVID-19 starting 14
days after the second IP dose. SARS-CoV-2 infection determined by
seroconversion assessed by bAb levels against SARS-CoV-2 as
measured by a ligand-binding assay specific to the SARS-CoV-2
nucleocapsid protein and with a negative NP swab sample for
SARS-CoV-2 at Day 1 (Section 8.1.1).
Immunogenicity Objective
(Secondary):
Immunogenicity Endpoints (Secondary):
To evaluate the immunogenicity of 2 doses of mRNA-1273 given 28
days apart.
• Geometric mean titer (GMT) of SARS-CoV-2 -specific
neutralizing antibody (nAb) on Day 1, Day 29, Day 57, Day 209, Day
394, and Day 759.
• Geometric mean fold rise (GMFR) of SARS-CoV-2-specific nAb
relative to Day 1 on Day 29, Day 57, Day 209, Day 394, and Day
759.
• Quantified levels or GMT of S protein-specific binding
antibody (bAb) on Day 1, Day 29, Day 57, Day 209, Day 394, and Day
759.
• GMFR of S protein -specific bAb relative to Day 1 on Day 29,
Day 57, Day 209, Day 394, and Day 759.
Exploratory Objectives
To evaluate the effect of mRNA-1273 on the viral infection
kinetics as measured by viral load at SARS-CoV-2 infection
diagnosis by RT-PCR and number of days from the estimated date of
SARS-CoV-2 infection until undetectable SARS-CoV-2 infection by
RT-PCR.
To assess VE to reduce the duration of symptoms of COVID-19.
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Abbreviations: AE = adverse event; AR = adverse reaction; bAb =
binding antibody; GMFR = geometric mean fold rise; GMT = geometric
mean titer; ICU = intensive care unit; MAAE = medically attended
adverse event; nAb = neutralizing antibody; NP = nasopharyngeal;
SAE = serious adverse event; VE = vaccine efficacy.
To evaluate VE against all-cause mortality.
To assess VE against burden of disease (BOD) due to
COVID-19.
To evaluate the genetic and/or phenotypic relationships of
isolated SARS-CoV-2 strains to the vaccine sequence.
To evaluate immune response markers after dosing with IP as
correlates of risk of COVID-19 and as correlates of risk of
SARS-CoV-2 infection.
To conduct additional analyses related to furthering the
understanding of SARS-CoV-2 infection and COVID-19, including
analyses related to the immunology of this or other vaccines,
detection of viral infection, and clinical conduct.
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4. STUDY DESIGN
4.1. General Design This is a Phase 3, randomized, stratified,
observer-blind, placebo-controlled study to evaluate the efficacy,
safety, and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine compared
to placebo in adults 18 years of age and older who have no known
history of SARS-CoV-2 infection but whose locations or
circumstances put them at appreciable risk of acquiring COVID-19
and/or SARS-CoV-2 infection. Figure 1 shows the study flow and
Appendix 1 (Section 11.1) displays the planned Schedules of Events
(SoEs).
Approximately 30,000 participants will be randomly assigned to
receive doses of either 100 µg of mRNA-1273 vaccine or a placebo
control in a 1:1 randomization ratio. Assignment will be stratified
by age and health risk (Section 6.2.1.1). This is a case-driven
study and thus final sample size of the study will depend on the
actual attack rate of COVID-19.
All participants will be assessed for efficacy and safety
endpoints and provide a nasopharyngeal (NP) swab sample and blood
sample before the first and second dose of IP in addition to a
series of post-dose blood samples for immunogenicity through 24
months after the second dose of IP. Efficacy assessments will
include surveillance for COVID-19 with RT-PCR confirmation of
SARS-CoV-2 infection after the first and second dose of IP. As
noted above, this is a case-driven study: if the prespecified
criteria for early efficacy are met at the time of either interim
analysis (IA) or overall efficacy at the primary analysis, a final
study report describing the efficacy and safety of mRNA-1273 will
be prepared based on the data available at that time. In the event
that success criteria are met either at the time of the interim
analyses or when the total number of cases toward the primary
endpoint have accrued, participants will continue to be followed in
a blinded fashion until Month 25, to enable assessment of long-term
safety and durability of VE (Figure 2). If the study concludes
early, all participants will be requested to provide a final blood
sample at the time of study conclusion.
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Figure 2: Event/Case-Driven Study with 24 Months of Planned
Follow-Up
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All participants may have up to 7 scheduled clinic visits,
including Screening, Day 1, Day 29,
Day 57, Day 209, Day 394 and Day 759 (Section 11.1). Each
participant will receive 2 doses of
IP by 0.5 mL intramuscular (IM) injection, the first on Day 1
and the second on Day 29. An NP
swab sample will be collected prior to the first and second dose
of IP, for evaluation by RT-PCR.
To preserve observer blinding, only delegated unblinded study
personnel responsible for study
vaccine preparation, administration and/or accountability will
have knowledge of study treatment
assignment (Section 6.2.8.1).
Participants will be given an electronic diary (eDiary) to
report solicited ARs for 7 days after each
dose of IP and to prompt an unscheduled clinic visit for
clinical evaluation and NP swab sample if
a participant experiences any symptoms of COVID-19. Participants
will use the eDiary to report
solicited ARs for 7 days after each dose of IP and weekly eDiary
prompts (every 7 days) to elicit
an unscheduled Illness Visit if the participant is experiencing
COVID-19 symptoms. All
participants will receive safety calls on Day 8, Day 15, Day 22,
Day 36, and Day 43 that will serve
both to monitor for unsolicited AEs and to monitor for symptoms
of COVID-19.
Safety telephone calls and eDiary safety prompts will be
performed in conjunction with
surveillance for COVID-19 according to the SoEs (Section 11.1)
and are intended to capture SAEs,
MAAEs, AEs leading to withdrawal, concomitant medications
associated with these events,
receipt of non-study vaccinations, and pregnancy (Section
8.2.1). If an eDiary prompt results in
identification of a relevant safety event, a follow-up safety
call will be triggered.
Surveillance for COVID-19 will be performed through weekly
contacts with the participant via a
combination of telephone calls and completion of an eDiary
starting at Day 1 through the end of
the study (Section 11.1, Section 8.1.2). Participants with
symptoms of COVID-19 lasting at least
48 hours (except for fever and/or respiratory symptoms) will
return to the clinic or will be visited
at home by medically qualified site staff within 72 hours to
collect an NP swab sample for RT-
PCR testing for SARS-CoV-2 and other respiratory pathogens, or
alternatively, if a clinic or home
visit is not possible, will submit a saliva (or nasal swab)
sample for SARS-CoV-2 RT-PCR testing
(Section 8.1.1).
All study participants who experience COVID-19 symptoms and
subsequently present for an
Illness Visit (in-clinic or at home) will be given an
instruction card listing symptoms and severity
grading system along with a thermometer, an oxygen saturation
monitor, and saliva collection
tubes. The list of symptoms is presented in Section 8.1.2 and
the severity scoring system is
presented in Section 8.1.3. Study participants will be contacted
by the investigator (or
appropriately delegated study staff) daily with telemedicine
visits through Day 14 or until
symptoms have resolved, whichever is later. During the
telemedicine visit (preferably done in the
evening), the participant will be asked to verbally report the
severity of each symptom, their
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highest body temperature and lowest oxygen saturation for that
day, and the investigator will
determine if medical attention is required due to worsening of
COVID-19 symptoms. (Table 17).
Study participants will collect their own saliva (or nasal swab)
sample on 3, 5, 7, 9, 14, and 21
days after the initial Illness Visit meeting criteria for
COVID-19 (defined as the date of onset of
symptoms and positive virologic test). Finally, a convalescent
visit will be scheduled
approximately 28 days after the initial Illness Visit. At this
visit, a saliva (or nasal swab) sample
will be collected and a blood sample will be drawn for
immunologic assessment of SARS-CoV-2
infection.
At each dosing visit, participants will be instructed (Day 1) or
reminded (Day 29) on how to
document and report solicited ARs in the eDiary provided.
Solicited ARs will be assessed for
7 days after each IP d